Ophthalmic compound with extended dwell time on the eye

ABSTRACT

Ophthalmic composition with prolonged residence time on the eye, in particular in the form of a gel which can be administered as drops, of an ointment or the like, containing a free-flowing vehicle with increased viscosity and a preservative, and, where appropriate, one or more active ingredients and conventional additives such as tonicity agents, substances to adjust the pH etc. The preservative is essentially formed according to the invention by a benzyllauryldimethylammonium salt. The invention furthermore relates to the use of a benzyllauryldimethylammonium salt as preservative for producing ophthalmic compositions intended for repeated use over lengthy periods and/or formulated for a lengthy residence time on the eye after each use, whereby irritation and/or damage to the tissue of the eye are avoided.

[0001] The invention relates to an ophthalmic composition with prolongedresidence time on the eye, in particular in the form of a gel which canbe administered as drops, of an ointment or the like, containing afree-flowing vehicle with increased viscosity and a preservative, and,where appropriate, one or more active ingredients and conventionaladditives such as tonicity agents, substances to adjust the pH etc. Theinvention additionally relates to the use of abenzyllauryldimethylammonium salt for producing ophthalmic compositions.

[0002] Ophthalmic compositions may, like other pharmaceutical productstoo, be contaminated by microorganisms of a wide variety of species. Thepossibility of such microorganisms entering the eye and getting onto themucosa of the eye on use of the ophthalmic composition must be avoided.Ophthalmic products must therefore comply with strict sterilityrequirements. This is why products of this type are always producedunder sterile conditions.

[0003] In order to increase the sterility and, in particular, the shelflife of ophthalmic products which are not intended for immediate use,preservatives are added to them. On the one hand, the latter must have asufficiently microbioidal effect to ensure the permanent sterility ofthe product, and on the other hand they must not themselves lead toirritation or tissue damage in the eye, which is, after all, oftenalready damaged.

[0004] These requirements are particularly crucial in the case ofophthalmic compositions which must be used repeatedly over lengthyperiods (one or more days or longer) so that a permanent level ofpreservative is set up in the eye. In this case the risk of irritationor even tissue damage by the preservative is particularly great.

[0005] This is similarly true of those ophthalmic compositions whichshow prolonged (by comparison with products which can easily be washedout by tear fluid, such as, for example, conventional aqueous droppersolutions) residence time on or in the eye after a single use. Productsof this type are, with regard to their consistency, adjusted to have anincreased viscosity. One example are aqueous products which aregelatinously thickened by adding water-soluble polymers, in particulargels which can be administered as drops. Another example are thewell-known ointments, usually in the form of spreadable emulsions.

[0006] Preservatives used for such purposes are, for example,thiomersal, cetrimide and similar substances.

[0007] Another preservative which is frequently suggested for ophthalmicproducts is benzalkonium chloride.

[0008] Benzalkonium chloride is the international nonproprietory namefor N-alkyl-N-benzyl-N,N-dimethyl-ammonium chloride with alkyl radicalsbetween C₈H₁₇ and C₁₈H₃₇. Benzalkonium chloride is normally obtainedfrom natural fats or oils and is a mixture of varying composition,depending on the raw materials used, of the quaternary compoundsdescribed above.

[0009] Unless other indicated, the term “benzalkonium” in thisapplication always means such a mixture with different alkyl radicals,with the number of carbon atoms in the alkyl radical varying from C₈ toC₁₈.

[0010] U.S. Pat. No. 4,053,628 discloses a clear solution of sodiumcromoglicate to which a large number of preservatives can be added.Suggested and exemplified besides thiomersal, cetrimide, benzetkoniumchloride and others is also benzalkonium chloride. The possibility ofadjusting the viscosity of such solutions is mentioned in general;however, the examples relate exclusively to solutions withoutviscosity-modifying additives. The risk of eye irritation due to thepreservative is not mentioned in this publication.

[0011] U.S. Pat. No. 4,271,143 has disclosed the use of benzalkoniumchloride as preservative in an ophthalmic gel for delayed release ofactive ingredient. There is no report of eye irritation with theenvisaged long residence time in the eye. The tests on the eye describedin U.S. Pat. No. 4,271,143 each lasted only a few hours. This ispossibly the reason why the problems which occur with such gels onprolonged use apparently were not observed.

[0012] Benzalkonium chloride has excellent antiseptic properties even inophthalmic preparations, especially in aqueous ophthalmic preparations.However, benzalkonium chloride is, as has emerged since publication ofthe abovementioned patents, poorly tolerated and may lead to irritationand even damage of the eye. B. Lopez et al. (Current Eye Research, 1991,10 (7) 645 to 656) report on the injurious effect of preservatives insimulated tear fluids on the cornea of rabbits. The effect of tearfluids preserved with 0.01%. benzalkonium chloride, 0.001% polyquat or0.004% thiomersal was related to that in a comparison group in which thesimulated tear fluid was used without preservative.

[0013] The measure chosen for the damage to the cornea was the increasein the ability to take up carboxyfluorescein. Simulated tears whichcontained polyquat or thiomersal brought about an increase in uptake ofone to four-fold. Simulated tears which contained benzalkonium chloridebrought about an increase in uptake of about 10 to 100-fold.

[0014] Checks by examination under the electron microscope demonstratedthat the increase in the ability to take up carboxyfluorescein wasassociated with increased cell damage in the cornea. As a result, urgentadvice against the use of benzalkonium salts in ophthalmic products wasgiven.

[0015] Individual benzalkonium components have attracted interestrecently. Thus, JP-A 1246227 describes a method for avoidingincompatibilities in liquid aqueous ophthalmic compositions, especiallyeye drops, which contain benzalkonium chloride. A large number ofmedicinal active ingredients shows incompatibility with benzalkoniumchloride in the dosage form as aqueous solution, leading to theformation and flocculation of soluble compounds. It is thereforeimpossible to use benzalkonium chloride as preservative in such aqueouscompositions. When virtually pure benzyllauryldimethylammonium chloride,that is to say the C₁₂ homologue from the benzalkonium, chloridemixture, is used, the described incompatibilities do not occur. It isthus possible to preserve eye drops whose active ingredient isincompatible with benzalkonium chloride by usingbenzyllauryldimethylammonium chloride.

[0016] This prior art has no relation to the problem of the lack oftolerability of benzalkonium chloride in the eye.

[0017] It is an object of the present invention to provide an ophthalmiccomposition of the type mentioned at the outset which is well toleratedby the eye, even on persistent exposure, and which overcomes thedisadvantages of the prior art without, at the same time, losing theadvantageous effects of the benzalkonium salts as preservatives.

[0018] Achievement of this object is made possible according to theinvention by the features of the independent claims.

[0019] The independent claims define advantageous embodiments of theinvention.

[0020] It has been found, surprisingly, that on use orbenzyllauryldimethylammonium salts as preservatives in ophthalmicproducts there is distinctly less or even no irritation and damage inthe eve, which are observed, however, on use or other preservatives,including benzalkonium chloride.

[0021] The invention therefore makes it possible in particular topreserve those ophthalmic compositions intended to have a prolongedresidence time on the eye by comparison with eye drops or the like. Itis possible, in particular in this way to produce gels which can beadministered as drops, ointments and the like to which the eye isexposed for a very long time after a single use, because they are onlyslowly washed out by the tear fluid, the preservative having all theadvantages of the known benzalkonium chloride but without eye-irritantor even eye-damaging effect.

[0022] The ophthalmic compositions according to the invention arepreferably those which have as vehicle an aqueous basis for a gel whichcan be administered as drops. In this case, a viscosity-increasingsynthetic or natural polymer in aqueous solution or aqueous dispersionwill be employed in a known manner.

[0023] Particularly suitable for this purpose are the carboxyvinylpolymers already known as gel formers, especially carboxypolymethyleneswhich are commercially available under the trade name “Carbopol”. It isalternatively possible to employ the ethylene/maleic anhydridecopolymers which are commercially available under the trade name “EMA”.

[0024] Particularly suitable natural polymers are the various cellulosederivatives which are in turn already known for ophthalmic gels,especially alkylcelluloses, hydroxycelluloses, hydroxyalkylcellulosesetc. It is possible with advantage to use in addition or as alternativenatural gums such as, for example, guar gum, xanthan gum etc. Otherexamples of natural polymers which can be used advantageously accordingto the invention are dextran and its derivatives.

[0025] It may be advantageous to formulate the ophthalmic compositionaccording to the invention as in principle a single-phase aqueous liquidin which the other ingredients occur in solution or as dispersedparticles.

[0026] It is an alternative and often even more advantageous possibilityto build up the composition as a two-phase liquid with an aqueous and ahydrophobic phase. Especially if the product contains particular activeingredients such as, for example, vitamin A, it will be preferred toprovide a continuous aqueous phase with droplets of the hydrophobicphase emulsified therein. Suitable as hydrophobic phase are oils, mediumchain-length triglycerides etc. Medium chain-length triglycerides willadvantageously be used as hydrophobic phase particularly in productswhich contain vitamin A as active ingredient.

[0027] The concentration of the benzyllauryldimethylammonium saltcorresponds to the usual concentrations employed for benzalkoniumchloride. The benzyllauryldimethylammonium salt is preferably simply thechloride.

[0028] Besides the ophthalmic compositions which have just beendescribed and have been formulated for prolonged residence time on theeye after each use, the advantage of the invention can also be utilizedfor those ophthalmic compositions which, although they contain noviscosity-increasing ingredients (which thus, delay washing out), mustbe used repeatedly over lengthy periods and thus likewise result in acontinuously elevated level of preservative in the eye. Products of thistype may also lead to irritation or even tissue damage if harmfulpreservatives are present, and therefore the advantage of the inventionmay also be used for such products by employing thebenzyllauryldimethylammonium salt as preservative in place of thesepreservatives.

[0029] Examples thereof are not only eye drops but also simulated tearfluid as in the test reported by Lopez et al.

[0030] The following examples serve merely to illustrate the inventionand represent no restriction whatsoever.

EXAMPLE 1

[0031] Ophthalmic Composition with 0.01% BenzyllauryldimethylammoniumChloride. Batch size: 2 kg Ingredients Amount in grams Carbopol 980 NF4.00 Benzyllauryldimethylammonium chloride 0.2000 Sorbitol 80.00 NaOH,solid 1.57 Water (remainder up to batch size)

EXAMPLE 2

[0032] Ophthalmic Composition with 0.005% BenzyllauryldimethylammoniumChloride. Batch size: 2 kg Ingredients Amount in grams Carbopol 980 NF4.00 Benzyllauryldimethylammonium chloride 0.1000 Sorbitol 80.00 NaOH,solid 1.57 Water (remainder up to batch size)

[0033] Long-term tests were carried out on experimental rabbits (CharlesRiver) with the compositions of Example 1 and 2. In parallel,comparative tests were carried out with a corresponding control group inwhich the compositions employed were in every respect the same butdiffered with regard to the preservative. Instead orbenzyllauryldimethylammonium chloride, on the one hand benzalkoniumchloride was used in the same concentration, and on the other hand,thiomersal (standard concentration)=40 μg/g was used.

[0034] The test lasted 5 weeks.

[0035] At the end of the test, seven or eight rabbits in the controlgroup treated with the composition with thiomersal as preservativeshowed severe irritation, and in some cases also damage to the eye.

[0036] the control group which received a product with benzalkoniumchloride as preservative, all the rabbits showed severe irritation, andsome showed damage to the tissue of the eye, at the end of theinvestigation.

[0037] By contrast, the ophthalmic compositions of Examples 1 and 2according to the invention led to no detectable irritation in the eye ofany rabbit at the end of the test period. Likewise, no tissue damagewhatsoever was observed.

1. Ophthalmic composition with prolonged residence time on the eye, inparticular in the form of a gel which can be administered as drops, ofan ointment or the like, containing a free-flowing vehicle withincreased viscosity and a preservative, and, where appropriate, one ormore active ingredients and conventional additives such as tonicityagents, substances to adjust the pH etc., characterized in that thepreservative is essentially formed by a benzyllauryldimethylammoniumsalt.
 2. Ophthalmic composition according to claim 1, characterized inthat the composition has as vehicle an aqueous base for a gel which canbe administered as drops.
 3. Ophthalmic composition according to claim 1or 2, characterized in that the vehicle of the composition contains atleast one viscosity-increasing synthetic or natural polymer in aqueoussolution or dispersion.
 4. Ophthalmic composition according to claim 3,characterized in that the polymer comprises a carboxyvinyl polymer, inparticular a carboxypolymethylene, or an ethylene/maleic anhydridecopolymer.
 5. Ophthalmic composition according to claim 3, characterizedin that the polymer comprises a cellulose derivative, a natural gum suchas xanthan, a dextran derivative or the like.
 6. Ophthalmic compositionaccording to any of claims 1 to 5, characterized in that the liquidportion of the composition is in the form of a single-phase aqueousliquid.
 7. Ophthalmic composition according to any of claims 1 to 5,characterized in that the liquid portion of the composition is in theform of a two-phase liquid, preferably as O/W emulsion.
 8. Ophthalmiccomposition according to any of claims 1 to 7, characterized in that thepreservative is benzyllauryldimethylammonium chloride.
 9. Ophthalmiccomposition according to any of claims 1 to 8, characterized in that theconcentration of the preservative based on the total amount of thecomposition is between 0.001% by weight and 0.5% by weight, preferablybetween 0.01% by weight and 0.05% by weight.
 10. Ophthalmic compositionaccording to any of claims 1 to 9, characterized in that the compositioncontains vitamin A as active ingredient.
 11. Ophthalmic compositionaccording to any of claims 1 to 10, characterized in that thecomposition comprises 0.001 to 1% by weight, preferably 0.1 to 0.5% byweight, of carboxypolyethylene, 0.0005 to 0.05% by weight, preferably0.001 to 0.01% by weight, of benzyllauryldimethylammonium chloride, 0.1to 10% by weight, preferably 1 to 5% by weight, of sorbitol, and alkalimetal hydroxide or acid to adjust a physiologically acceptable pH andotherwise water.
 12. Use of a benzyllauryldimethylammonium salt aspreservative for producing ophthalmic compositions intended for repeateduse over lengthy periods and/or formulated for a lengthy residence timeon the eye after each use, whereby irritation and/or damage to thetissue of the eye are avoided.
 13. Use of benzyllauryldimethylammoniumchloride according to claim
 12. 14. Use of the preservative according toclaim 12 or 13 for eye drops having a least one active ingredient. 15.Use of the preservative according to claim 12 or 13 for a simulated tearfluid.